Muscle Diseases Clinical Trials Roundtable Summary

Introduction

This roundtable was convened as part of a larger NIAMS effort to assess its support of clinical trials across the Institute’s mission areas. Goals include identifying needs and opportunities, as well as finding key steps for evaluating trials and the significance of individual studies in the broader context of future clinical needs. There were prior discussions on the subject at the 2009 NIAMS Scientific Retreat and with the NIAMS Advisory Council. A Council subcommittee is being created for further developments. Roundtable attendees canvassed their relevant communities in advance, to bring more than their own opinions to the meeting.

Needs

Participants spoke generally about the need to build the knowledge base in an effort to provide the foundation for future translational and clinical research. Most acknowledged that a greater fundamental understanding of healthy and diseased muscle biology is required. There have been significant advances in the pathophysiology of rare muscle diseases, such as some of the muscular dystrophies. However, investigations into more common muscle conditions and symptoms, for example, the mechanisms of pain and fatigue, as well as those involved in muscle atrophy due to aging, could potentially lend insights that would advance treatments for both common and rare diseases. Furthermore, research into the impact of exercise and nutrition could lead to preventive or therapeutic strategies. Identification of biomarkers for disease and co-morbidities were also mentioned.

Even in those diseases or conditions where interventions have been proposed or are being tested, further investigation is needed for continued development. It was pointed out, however, that interventions that exhibit efficacy in animal models often fail in clinical trials, which reinforces the rationale for a greater understanding of human muscle biology. Among the efforts mentioned as current or future needs, the following were discussed as areas of interest:

Stimulation of muscle regeneration

Inhibition of fibrosis

Inhibition of necrosis or apoptosis

Promotion of strength

Evaluation of genetic and/or environmental determinants

Opportunities

Among the group present, there was great enthusiasm for natural history studies. As the field proceeds with translational studies on many promising therapeutic strategies, it is well-recognized that a better understanding of the clinical features of muscle disease can lead to the design of more effective clinical trials. Such observational studies are especially needed to refine and validate effective biomarkers and other clinical outcome measures. Future genotyping efforts would also benefit from the characterization of cohorts across various diseases. Furthermore, the usefulness of sharing the data produced by unsuccessful and unpublished trials was discussed.

Also of interest was the opportunity and challenge of standardizing treatment protocols and outcome measures across all muscle diseases, and the establishment of a registry to document and track them. Because so many muscle diseases are rare, sharing this information could accelerate the production of data-driven treatments fueled by improved diagnostics and outcome measures.

As clinical trials in muscle diseases progress, the number of well-qualified investigators to carry out the studies may become rate limiting. In order to best leverage the scientific and clinical opportunities in the field, roundtable participants identified the need for greater awareness and education of the public, an enhancement of clinical training on muscle diseases for researchers, and the attraction of new investigators. Such efforts could lead to more accurate diagnoses and the opportunity for earlier intervention, when treatments become available.

Prioritization

The potential high impact and the high cost of clinical trials leads to an increased importance on prioritization strategies. Throughout the day, three similar approaches were embraced and discussed.

First, it was suggested that the Institute organize regular multi-disciplinary meetings, consisting of clinical trial researchers, along with basic and translational scientists, to consider the “readiness” of interventions for clinical trials. These meetings would serve to inform the Institute, but also provide opportunities to generate new ideas and collaborations. The research community could also be encouraged to focus on the most promising therapeutic strategies. It was envisioned that these meetings could generate broad strategies and promote the exchange of information between researchers and patients, across both rare and common diseases.

Another suggestion was to combine or support the collaboration of existing networks. Such communication and collaboration of clinical investigators would help to prioritize scientific opportunities, enhance mentoring, and ensure that an breakthrough in one disease area leads to leveraged advances in others.

Lastly, a plan was considered where clinical trial ideas would be nominated by the community and selected by the Institute to be developed into funding opportunities. The roundtable participants acknowledged that some investigators would be wary of volunteering their best ideas, but felt that the originator would always have an advantage during the review process. The group also debated the process by which nominated ideas would be selected for development.

Outcomes/Mechanisms

Participants acknowledged that, when applications for grants to support clinical trials are reviewed in study sections alongside those for basic research studies, the clinical applications may be disadvantaged. This concern stems from the belief that study sections tend to have more limited expertise in clinical research than in basic research. In addition, the recent emphasis on innovation in the review and funding process may be a hurdle for clinical research applications, which may be significant and well-designed, but must limit innovation in order to protect human subjects.

The Clinical and Translational Science Awards (CTSAs) have been a good step forward, providing basic infrastructure through shared resources and staff. They also allow for collaboration and a way to recruit new investigators, but it was felt that they are not a wholesale solution to all clinical needs.

One suggestion was the creation of standing advisory committees dedicated to clinical research in particular tissue or disease areas relevant to the Institute’s mission. These committees could help:

Bring various disciplines, ideas, and opportunities together by enhancing communication across disciplines

Identify needed infrastructure

Advise and mentor applicants and grantees

Survey stakeholders qualitatively and quantitatively

Provide prioritization and expert advice

The group discussed several different roles in which these committees could interact with the Institute. Also, it was noted that the selection of committee members and the distribution of committees across the Institute’s portfolio would be a significant challenge.

Our Mission

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.